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Molecular Progression of Genome-Related Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 13829

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Prof. Dr. Salvatore Saccone

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Guest Editor

Department Biological, Geological and Environmental Sciences, University of Catania, 95124 Catania, Italy
Interests: genetics; genomics; molecular cytogenetics; chromosomes; nuclear chromatin organization; evolutionary genetics; developmental genetics; forensic genetics; environmental mutagenesis; epigenetics
Special Issues, Collections and Topics in MDPI journals

Dr. Francesco Calì

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Guest Editor

Oasi Research Institute—IRCCS, Via Conte Ruggero 73, 94018 Troina, Italy
Interests: Mendelian diseases; neurological diseases; population genetics

Special Issue Information

Dear Colleagues,

Advancements in genomic technologies, such as next-generation sequencing, have revolutionized our ability to unravel the molecular basis of genome-related diseases. By analyzing genetic variations and mutations, the key genes and pathways involved in the development of several diseases have been identified. This knowledge has not only facilitated accurate diagnosis and personalized medicine but also opened avenues for innovative therapies targeting specific genetic aberrations. Our current capacity to rapidly analyze entire exome and genome sequences at an affordable cost has the potential to yield greater benefits, supporting the genetic investigation of complex diseases and generating opportunities which may arise from examining specific and distinct phenotypes.

Despite these significant strides, challenges remain, including the complexity of some genetic diseases and the need for more comprehensive databases to catalog genetic variants and their clinical implications. The definition of gene panels to analyze with NGS for diagnostic purposes is certainly a relevant subject in human health, considering the various diseases with a genetic basis of increasing interest such as, but not limited to, neurological or neuromuscular disorders, cardiomyopathies, and hereditary cancer syndromes and hematological disorders.

For this Special Issue, we invite researchers in the field to publish reviews or original research papers covering recent advances in the use of gene panels to detect mutations/variants related to the diagnosis of complex genetic diseases and improvements related to new tools for genomic analysis. Our aim is to have a Special Issue that presents up-to-date information on genomic analysis systems for complex genetic diseases and serves as a reference to researchers in the field and users of these technologies for diagnostic purposes.

Prof. Dr. Salvatore Saccone
Dr. Francesco Calì
Guest Editors

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Keywords

next-generation sequencing
genetic diseases
multifactorial diseases
diagnostic tolls
human health

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Published Papers (9 papers)

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Research

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16 pages, 1761 KiB

Open AccessArticle

Emerging Signatures of Hematological Malignancies from Gene Expression and Transcription Factor-Gene Regulations

by Daniele Dall’Olio, Federico Magnani, Francesco Casadei, Tommaso Matteuzzi, Nico Curti, Alessandra Merlotti, Giorgia Simonetti, Matteo Giovanni Della Porta, Daniel Remondini, Martina Tarozzi and Gastone Castellani

Int. J. Mol. Sci. 2024, 25(24), 13588; https://doi.org/10.3390/ijms252413588 - 19 Dec 2024

Viewed by 769

Abstract

Hematological malignancies are a diverse group of cancers developing in the peripheral blood, the bone marrow or the lymphatic system. Due to their heterogeneity, the identification of novel and advanced molecular signatures is essential for enhancing their characterization and facilitate its translation to new pharmaceutical solutions and eventually to clinical applications. In this study, we collected publicly available microarray data for more than five thousand subjects, across thirteen hematological malignancies. Using PANDA to estimate gene regulatory networks (GRNs), we performed hierarchical clustering and network analysis to explore transcription factor (TF) interactions and their implications on biological pathways. Our findings reveal distinct clustering patterns among leukemias and lymphomas, with notable differences in gene and TF expression profiles. Gene Set Enrichment Analysis (GSEA) identified 57 significantly enriched KEGG pathways, highlighting both common and unique biological processes across HMs. We also identified potential drug targets within these pathways, emphasizing the role of TFs such as CEBPB and NFE2L1 in disease pathophysiology. Our comprehensive analysis enhances the understanding of the molecular landscape of HMs and suggests new avenues for targeted therapeutic strategies. These findings also motivate the adoption of regulatory networks, combined with modern biotechnological possibilities, for insightful pan-cancer exploratory studies. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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11 pages, 1111 KiB

Open AccessArticle

The Influence of Genetic Polymorphisms in Cytochrome P450 (CYP1A1 and 2D6) Gene on the Susceptibility to Philadelphia Negative Chronic Myeloid Leukemia in Sudanese Patients

by Abozer Y. Elderdery, Hadeil M. E. Idris, Saud Nahar L. Alruwaili, Entesar M. Tebien, Abdullah Alsrhani, Fawaz O. Alenazy, Badr Alzahrani, Emad Manni, Ahmed M. E. Elkhalifa and Jeremy Mills

Int. J. Mol. Sci. 2024, 25(24), 13493; https://doi.org/10.3390/ijms252413493 - 17 Dec 2024

Viewed by 937

Abstract

The most frequent type of leukemia in Africa is chronic myeloid leukemia (CML). The genetic background of the rarer Philadelphia chromosome (Ph) Ph-ve (BCR-ABL-ve) subform of CML is largely unknown in African patients. Therefore, in this study, we aimed to investigate the role of CYP1A1 and 2D6 SNPs in the pathogenesis of Ph-ve CML in the Sudanese population. A total of 126 patients were selected for analysis. DNA was isolated from Ph-ve CML patients and a control group for PCR-RFLP analysis of SNPs CYP1A1*2C and CYP2D6*4. The CYP1A1 gene significantly expressed the GG variant genotype (p < 0.05) in 23.1% of the Ph-ve CML patients and 8% of the control group. In contrast, the CYP2D6 GA genotype was strongly associated with a reduced risk of developing Ph-ve CML (p < 0.005) with a frequency of 50% in Ph-ve patients and 93% in the control group. CYP1A1 GG polymorphism was prevalent among patients with Ph-ve CML, suggesting its role in disease development. CYP2D6 GA (IM) polymorphism was uncommon among patients, compared with the control group, possibly indicating a protective role of the polymorphisms from Ph-ve CML. This study demonstrates an association between key metabolic SNPs and Ph-ve CML and highlights the role that altered xenobiotic metabolism may play in the development of several human leukemias. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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14 pages, 2031 KiB

Open AccessArticle

Changes in Gene Expression Related to Atopic Dermatitis in Mothers and Infants Following VOC Exposure

by Seung Hwan Kim, So Yeon Yu, Jeong Hyeop Choo, Jin Kyeong Kim, Jihyun Kim, Kangmo Ahn and Seung Yong Hwang

Int. J. Mol. Sci. 2024, 25(23), 12827; https://doi.org/10.3390/ijms252312827 - 28 Nov 2024

Viewed by 852

Abstract

Environmental pollutants, particularly volatile organic compounds (VOCs), are associated with various diseases, including atopic dermatitis (AD). However, despite numerous studies on AD, there is a lack of research on the impact of various environmental exposures on mothers and infants. This study, therefore, investigated the effects of maternal exposure to specific VOCs (toluene, xylene, and benzene) on the expression of AD-related genes in mothers and their infants. RNA expression levels and DNA methylation patterns were analyzed to examine the correlation between environmental exposures and AD. A multi-omics approach integrating gene expression and methylation data was additionally employed to gain a broader understanding of the genetic impact of VOC exposure. Network analysis revealed significant changes in gene expression associated with AD. For example, maternal exposure to toluene resulted in the upregulation of AQP10, which is linked to keratinocyte dysfunction, and in infants, the genes IL31RA and CCL20 were notably affected, both of which play critical roles in immune response and skin barrier function. In mothers exposed to xylene, the histamine receptor gene HRH1 was identified as a key player in influencing AD through its role in skin barrier recovery, while infants exhibited consistent network responses with upregulation of IL31RA and downregulation of TIGIT, reflecting a shared response across different xylene isomers. Interestingly, infants exposed to xylene isomers displayed nearly identical gene network patterns, suggesting developmental resistance to diverse environmental factors. No significant gene changes were identified in the benzene-exposed group. These findings suggest that exposure to specific VOCs may have different effects on gene expression related to AD, highlighting the complexity of how environmental factors contribute to disease development. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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15 pages, 3932 KiB

Open AccessArticle

Whole Genome Sequencing Analysis of Model Organisms Elucidates the Association Between Environmental Factors and Human Cancer Development

by Shinya Hasegawa, Yutaka Shoji, Mamoru Kato, Asmaa Elzawahry, Momoko Nagai, Min Gi, Shugo Suzuki, Hideki Wanibuchi, Sachiyo Mimaki, Katsuya Tsuchihara and Yukari Totsuka

Int. J. Mol. Sci. 2024, 25(20), 11191; https://doi.org/10.3390/ijms252011191 - 17 Oct 2024

Viewed by 1130

Abstract

Determining a novel etiology and mechanism of human cancer requires extraction of characteristic mutational signatures derived from chemical substances. This study explored the mutational signatures of N-nitroso bile acid conjugates using Salmonella strains. Exposing S. typhimurium TA1535 to N-nitroso-glycine/taurine bile acid conjugates induced a predominance of C:G to T:A transitions. Two mutational signatures, B1 and B2, were extracted. Signature B1 is associated with N-nitroso-glycine bile acid conjugates, while Signature B2 is linked to N-nitroso-taurine bile acid conjugates. Signature B1 revealed a strong transcribed strand bias with GCC and GCT contexts, and the mutation pattern of N-nitroso-glycine bile acid conjugates in YG7108, which lacks O⁶-methylguanine DNA methyltransferases, matched that of the wild-type strain TA1535, suggesting that O⁶-methyl-deoxyguanosine contributes to mutations in the relevant regions. COSMIC database-based similarity analysis revealed that Signature B1 closely resembled SBS42, which is associated with occupational cholangiocarcinoma caused by overexposure to 1,2-dichlolopropane (1,2-DCP) and/or dichloromethane (DCM). Moreover, the inflammatory response pathway was induced by 1,2-DCP exposure in a human cholangiocyte cell line, and iNOS expression was positive in occupational cholangiocarcinomas. These results suggest that 1,2-DCP triggers an inflammatory response in biliary epithelial cells by upregulating iNOS and N-nitroso-glycine bile acid conjugate production, resulting in cholangiocarcinoma via DNA adduct formation. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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19 pages, 4565 KiB

Open AccessArticle

Novel Acetamide-Based HO-1 Inhibitor Counteracts Glioblastoma Progression by Interfering with the Hypoxic–Angiogenic Pathway

by Agata Grazia D’Amico, Grazia Maugeri, Luca Vanella, Valeria Consoli, Valeria Sorrenti, Francesca Bruno, Concetta Federico, Antonino Nicolò Fallica, Valeria Pittalà and Velia D’Agata

Int. J. Mol. Sci. 2024, 25(10), 5389; https://doi.org/10.3390/ijms25105389 - 15 May 2024

Cited by 2 | Viewed by 1478

Abstract

Glioblastoma multiforme (GBM) represents the deadliest tumor among brain cancers. It is a solid tumor characterized by uncontrolled cell proliferation generating the hypoxic niches in the cancer core. By inducing the transcription of hypoxic inducible factor (HIF), hypoxia triggers many signaling cascades responsible for cancer progression and aggressiveness, including enhanced expression of vascular endothelial growth factor (VEGF) or antioxidant enzymes, such as heme oxygenase-1 (HO-1). The present work aimed to investigate the link between HO-1 expression and the hypoxic microenvironment of GBM by culturing two human glioblastoma cell lines (U87MG and A172) in the presence of a hypoxic mimetic agent, deferoxamine (DFX). By targeting hypoxia-induced HO-1, we have tested the effect of a novel acetamide-based HO-1 inhibitor (VP18/58) on GBM progression. Results have demonstrated that hypoxic conditions induced upregulation and nuclear expression of HO-1 in a cell-dependent manner related to malignant phenotype. Moreover, our data demonstrated that the HO-1 inhibitor counteracted GBM progression by modulating the HIFα/HO-1/VEGF signaling cascade in cancer cells bearing more malignant phenotypes. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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13 pages, 1399 KiB

Open AccessArticle

APOE ε2-Carriers Are Associated with an Increased Risk of Primary Angle-Closure Glaucoma in Patients of Saudi Origin

by Altaf A. Kondkar, Taif A. Azad, Tahira Sultan, Tanvir Khatlani, Abdulaziz A. Alshehri, Rakesh Radhakrishnan, Glenn P. Lobo, Ehab Alsirhy, Faisal A. Almobarak, Essam A. Osman and Saleh A. Al-Obeidan

Int. J. Mol. Sci. 2024, 25(8), 4571; https://doi.org/10.3390/ijms25084571 - 22 Apr 2024

Cited by 1 | Viewed by 1537

Abstract

This study investigated the association between apolipoprotein E (APOE) gene polymorphisms (rs429358 and rs7412) and primary angle-closure glaucoma (PACG) and pseudoexfoliation glaucoma (PXG) in a Saudi cohort. Genotyping of 437 DNA samples (251 controls, 92 PACG, 94 PXG) was conducted using PCR-based Sanger sequencing. The results showed no significant differences in the allele and genotype frequencies of rs429358 and rs7412 between the PACG/PXG cases and controls. Haplotype analysis revealed ε3 as predominant, followed by ε4 and ε2 alleles, with no significant variance in PACG/PXG. However, APOE genotype analysis indicated a significant association between ε2-carriers and PACG (odds ratio = 4.82, 95% CI 1.52–15.26, p = 0.007), whereas no notable association was observed with PXG. Logistic regression confirmed ε2-carriers as a significant predictor for PACG (p = 0.008), while age emerged as significant for PXG (p < 0.001). These findings suggest a potential role of ε2-carriers in PACG risk within the Saudi cohort. Further validation and larger-scale investigations are essential to elucidate the precise role of APOE in PACG pathogenesis and progression. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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18 pages, 2274 KiB

Open AccessArticle

Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies

by Luigi Vetri, Francesco Calì, Salvatore Saccone, Mirella Vinci, Natalia Valeria Chiavetta, Marco Carotenuto, Michele Roccella, Carola Costanza and Maurizio Elia

Int. J. Mol. Sci. 2024, 25(2), 1146; https://doi.org/10.3390/ijms25021146 - 17 Jan 2024

Cited by 7 | Viewed by 2278

Abstract

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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12 pages, 5257 KiB

Open AccessArticle

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy

by Mirella Vinci, Carola Costanza, Rosanna Galati Rando, Simone Treccarichi, Salvatore Saccone, Marco Carotenuto, Michele Roccella, Francesco Calì, Maurizio Elia and Luigi Vetri

Int. J. Mol. Sci. 2023, 24(22), 16436; https://doi.org/10.3390/ijms242216436 - 17 Nov 2023

Cited by 14 | Viewed by 1917

Abstract

Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as “SNAREopathies”, including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles’ exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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Review

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10 pages, 1438 KiB

Open AccessReview

Genotype–Phenotype Correlation of GNAS Gene: Review and Disease Management of a Hotspot Mutation

by Lorenzo Cipriano, Rosario Ferrigno, Immacolata Andolfo, Roberta Russo, Daniela Cioffi, Maria Cristina Savanelli, Valeria Pellino, Antonella Klain, Achille Iolascon and Carmelo Piscopo

Int. J. Mol. Sci. 2024, 25(20), 10913; https://doi.org/10.3390/ijms252010913 - 10 Oct 2024

Cited by 1 | Viewed by 1668

Abstract

Defects of the GNAS gene have been mainly associated with pseudohypoparathyroidism Ia. To date, pathogenic missense, frameshift, non-sense and splicing variants have been described in all the 13 exons of the GNAS gene. Of them, a specific mutation, namely the 4 bp deletion c.565_568delGACT, is currently considered a mutation hotspot. Recent articles performed genotype–phenotype correlations in patients with GNAS-related pseudohypoparathyroidism Ia (PHP1a) but a specific focus on this hotspot is still lacking. We reported two cases, from our department, of PHP1a associated with c.565_568delGACT deletion and performed a literature review of all the previously reported cases of the 4 bp deletion hotspot. We found a higher prevalence of brachydactyly, round face, intellectual disability and subcutaneous/heterotopic ossifications in patients with the c.565_568delGACT as compared to the other variants in the GNAS gene. The present study highlights the different prevalence of some clinical features in patients with the c.565_568delGACT variant in the GNAS gene, suggesting the possibility of a personalized diagnostic follow-up and surveillance for these patients. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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